A signaling pathway for transcriptional regulation of sleep amount in mice

In mice and humans, sleep quantity of individuals are governed by genetic factors and exhibit age-dependent variations. However, the core molecular pathways and effector mechanisms that regulate sleep time in mammals remain unclear. Here, we characterize a major signaling pathway for transcriptional regulation of sleep quantity in mice by adeno-associated virus-mediated somatic genetics analysis. Adult brain chimeric-knockout of LKB1 kinase, an activator of AMPK-related protein kinase SIK3/SLEEPY, markedly reduces non-rapid eye movement sleep (NREMS) amount and delta power–a measure of sleep depth. Downstream of LKB1-SIK3 pathway, gain or loss-of-function of histone deacetylases HDAC4/5 in adult brain neurons causes bidirectional changes of NREMS amount and delta power. Phosphorylation of HDAC4/5 is regulated in relation to sleep need, and HDAC4 specifically regulates sleep amount in posterior hypothalamus. Genetic and transcriptomic studies reveal that HDAC4 cooperates with CREB in both transcriptional and sleep regulation. These findings introduce the concept of signaling pathways targeting transcription modulators to regulate daily sleep amount and demonstrate utility of somatic genetics in mouse sleep research. 1. Differential expression analysis between ABC-HDAC4CA and mCherry mouse cortex, hypothalamus and thalamus. 2. Differential expression analysis between ABC-CREB and mCherry mouse cortex, hypothalamus and thalamus. 3. Differential expression analysis between Sik3E13∆/+ and WT mouse cortex, hypothalamus and thalamus at ZT0.5 or ZT12.5. 4. Differential expression analysis between HDAC4CA and eGFP expressed Sik3E13∆/+ mouse cortex, hypothalamus and thalamus at ZT0.5 or ZT12.5. 5. Differential expression analysis between CREB and eGFP expressed Sik3E13∆/+ mouse cortex, hypothalamus and thalamus at ZT12.5. Four biological replicates were prepared for mRNA profiles.